Drug delivery system and method for controlled and continuous delivery of drugs into the brain by bypassing the blood brain barrier.

ABSTRACT

The present invention provides devices and methods for controlled and continuous delivery of drugs into the brain by bypassing the blood brain barrier, without the need for any surgical manipulation of the brain. The respiratory mucosa in the maxillary sinus or in the nasal region is surgically accessed from the oral or maxillofacial region through a window made on the bone overlying the mucosa. The device is used to deliver drugs in a continuous and controlled manner either beneath or above the respiratory mucosa depending on the clinical requirements, drug formulation and the volume of drug used. The drug distributes into the brain from the delivery site by bypassing the blood brain barrier without causing any significant increase of the drug in the peripheral circulation. The device can be used for continuous and controlled drug delivery into the brain by bypassing the blood brain barrier for a number of medical conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims foreign priority from the Indian Complete PatentApplication No: 201641014398 filed in India on Apr. 26, 2016 and theIndian Complete Patent Application No: 3904/CHE/2015 filed in India onJul. 30, 2015.

Application No: 3904/CHE/2015 filed in India on Jul. 30, 2015 is apatent of addition to the Indian Complete Patent Application No:1430/CHE/2014 filed in India on Mar. 19, 2014. The mentionedapplications are incorporated herein by reference in their entirety.

REFERENCES

U.S.PATENT DOCUMENTS 9,216,161 B2 December 2015 Frey, II et al 9,211,273B2 December 2015 Frey, II et al 9,211,272 B2 December 2015 Frey, II etal 9,205,066 B2 December 2015 Hanson II et al 8,622,993 B2 January 2014Frey, II et al. 8,501,691 B2 August 2013 Yeomans et al. 8,258,096 B2September 2012 Yeomans et al 9,249,424 B2 February 2016 Wolf et al9,302,124 B2 April 2016 Konafagu et al 9,221,867 B2 December 2015Beliveau et al 8,858,950 B2 October 2014 Pardridge et al 8,733,342 B2May 2014 Giroux et al 8,715,659 B2 May 2014 Muruganandam et al 8,629,114B2 January 2014 Walz 8,497,246 B2 July 2013 Pardridge et al 8,415,319 B2April 2013 Kaemmerer 8,288,444 B2 October 2012 Lilienfeld et al8,119,611 B2 February 2012 Kaemmerer 8,058,251 B2 November 2011Kaemmerer 7,981,417 B2 July 2011 Shusta et al 7,972,308 B2 July 2011Putz 7,905,229 B2 March 2011 Giroux et al 7,803,400 B2 September 2010Nelson et al 7,744,879 B2 June 2010 Shusta et al 7,682,627 B2 March 2010Nelson et al 7,618,948 B2 November 2009 Kaemmerer 7,388,079 B2 June 2008Pardridge et al 7,358,068 B2 June 2008 Vaillant et al

FIELD OF THE INVENTION

The present invention relates to devices, systems and methods forcontrolled and continuous delivery of drugs into the brain by bypassingthe blood brain barrier, without the need for any surgical manipulationof the brain. The drug is delivered using an implantable device eitherbeneath or above the respiratory mucosa, by surgically creating a windowon the bone overlying the respiratory mucosa and accessing theconnective tissue side of the respiratory mucosal lining from the oralor maxillofacial region. The locally delivered drug may be transportedthrough the neural, vascular or lymphatic routes or a combination ofthese routes and delivered into the brain by bypassing the blood brainbarrier in human or animal patients. Accordingly the present inventionrelates to the fields of drug delivery and medicine especially Oral andMaxillofacial Surgery, Neuroanatomy and Neurology.

BACKGROUND OF THE INVENTION

The present invention relates to implantable devices, systems andmethods for controlled and continuous delivery of drugs into the brainby bypassing the blood brain barrier, without the need for any surgicalmanipulation of the brain

The brain has good blood supply. As the brain is a highly sensitiveorgan, the cells lining the blood vessels in the brain are tightlyarranged without any spaces between them to form a natural barriercalled as the blood brain barrier. This blood brain barrier preventsentry of any foreign substance into the brain and thereby protects thebrain. At the same time, it also prevents drugs present in thecirculating blood from entering into the brain. Hence it is notpractically possible to treat many medical conditions of the brain, eventhough the cause of the disease and the drug required for the treatmentare known, because of the simple reason that the drug cannot enter thebrain.

In the recent years, more information about the central nervous systemand blood brain barrier have been unraveled using advanced molecular andimaging techniques. This has led to identification of newer therapeutictargets for drugs at the molecular level. New drugs have also beendeveloped which can act on these molecular targets. Though in vitrostudies and pre-clinical studies are positive for these drugs, they showhigh failure rate when administered in humans. This is mainly becausethe drugs are not able to enter the brain in the required therapeuticconcentration to produce the pharmacologic effects. In fact, 98% ofsmall drugs and almost 100% of large drugs are not able to cross thebarrier. Hence there is a need for an effective drug delivery routewhich can deliver the drug into the brain at the right concentration ina continuous but controlled manner.

The methods available today for delivering drugs directly into the brainare mostly invasive. The methods include placement of micro-catheters orimplants into the brain or use of various techniques to open the bloodbrain barrier. These techniques however make the brain also prone toinfection as the brain gets exposed to the external environment.Advancement in the field of proteomics and genomics has led to discoveryof therapeutic targets at the level of molecules or genes in the brain,leading to development of newer drugs. But these drugs also getdestroyed when given orally. Hence alternative routes for drug deliveryare the need of the hour.

Recent studies have shown that the nasal route can be used as anon-invasive route to deliver the drugs directly to the brain. But thisroute has limitations because controlled and continuous delivery ofdrugs at predetermined rates has not yet been achieved. The drugs alsohave to withstand mucociliary clearance, local enzymatic degradation andcross the epithelial layer before they reach the underlying connectivetissue for further absorption. Hence only a smaller quantity of thetotal drug that is delivered, is finally absorbed. Drugs modified forendogenous transport mediated delivery across the blood brain barrier,using the naturally occurring molecular transport mechanisms at theendothelial cell have been developed for a few medical conditions. Yetthe concentration of the drug delivered across the blood brain barrierusing this technique is not predictable. Protein mediated drug deliveryand viral mediated gene therapy may also induce immune mediatedcomplications. Systemic routes like intra venous or intra-arterial needhigh concentration of the drug. Moreover intra-arterial route results insevere complications. Therefore an effective alternative route which candeliver drugs into the brain in a controlled and continuous manner, fora long period of time, without any complications or discomfort to thepatient holds immense potential.

Trigeminal nerve supplies the nasal respiratory mucosa and the maxillarysinuses and relays at the nuclei in the brainstem. Cerebrospinal fluidhas also been found to drain through nasal lymphatics. The nasallymphatic channels are free of valves and can hence be used for drugdelivery. Blood vessels in the nasal and maxillary sinus region may alsotransfer the drugs to the brain. The veins from the maxillary sinus andthe nasal region drain into the pterygoid venous plexus which is furtherconnected to the cavernous sinus. Therefore the drugs delivered locallyin these regions can drain reach the pterygoid venous plexus and befurther transferred into the cavernous sinus. The drugs can then enterthe cerebral circulation at higher concentration without causingsystemic toxicity either through the counter current mechanism at thecavernous sinus or through the perivascular pathways. Hence the drugdelivered locally beneath the respiratory mucosa, may be transportedfrom the nasal and maxillary sinus region through the neural, lymphaticand the vascular routes into the brain by bypassing the blood brainbarrier.

The air circulation in the maxillary sinus is unique. The maxillarysinus fills with air during expiration and is emptied of air duringinspiration. Hence a drug delivered into the maxillary sinus byperforating the sinus lining mucosa from the connective tissue side canbe easily inhaled when the air inside the maxillary sinus is emptiedduring inspiration. The drug can further come in contact with the nasalrespiratory and olfactory mucosa for absorption. Also the mucus on themaxillary sinus lining mucosa is moved towards the ostium opening andinto the middle meatus of nose because of the muco-ciliary action. Hencethe drug delivered on the maxillary sinus lining mucosa can also betransported by the muco-ciliary action through the ostial opening intothe middle meatus and onto the nasal respiratory mucosa. Because of theincreased retention time of the drug on the mucosal surface, higherquantity of the drug can be inhaled and be deposited on the nasalrespiratory and olfactory mucosa for further absorption into theunderlying connective tissue.

Goblet cells in the maxillary sinus lining mucosa secrete mucus. Drugscan be engineered for uptake from the connective tissue into the gobletcells, for further secretion along with mucus by the goblet cells. Thiscan result in mucus loaded with high concentration of drug molecule forinhalation. The inhaled drug can be deposited on the nasal respiratorymucosa and olfactory mucosa for further absorption.

It therefore would be desirable to deliver drugs into the brain using adevice without any need for surgical manipulation of the brain. It wouldfurther be desirable to provide a device which can be surgicallyimplanted with its delivery tip located beneath or above the respiratorymucosa, by surgically creating a window on the bone overlying therespiratory mucosa and accessing the connective tissue side of therespiratory mucosal lining from the oral or maxillofacial region. Itwould also be desirable to deliver the drug in a controlled andcontinuous manner by connecting the device to an external drug infusionpump. The drug from the respiratory mucosa can be transported throughthe neural, vascular, lymphatic, inhalation or a combination of allthese routes and delivered into the brain by bypassing the blood brainbarrier and without causing any systemic toxicity.

SUMMARY OF THE INVENTION

One aspect of the present invention provides a drug delivery system fordelivering drugs into the brain, by bypassing the blood brain barrier.The drug delivery system comprises an implantable hollow device made oftitanium or any other biocompatible material, intended for placementinto the bone overlying the respiratory mucosa of the maxillary sinusand the nasal cavity and a drug delivery assembly made of abiocompatible material intended for transferring therapeutic agents froman external drug reservoir into the central lumen of the implantablehollow device. An external drug infusion pump is used for providingcontinuous and controlled drug delivery of therapeutic agents from theexternal drug reservoir into the central lumen of the implantable hollowdevice.

Another aspect of the invention provides a method of drug delivery intothe brain by bypassing the blood brain barrier. The device is used todeposit the drug beneath the respiratory mucosa, by surgically creatinga bone window on the overlying bone and accessing the connective tissueside of the respiratory mucosal lining from the oral or maxillofacialregion. The drug delivered locally beneath the respiratory mucosa, maybe transported from the nasal and maxillary sinus region through theneural, lymphatic and the vascular routes into the brain by bypassingthe blood brain barrier.

An alternative method of drug delivery into the brain by bypassing theblood brain barrier is provided wherein the tip of the drug deliverydevice is placed into the maxillary sinus and above the level of theepithelial lining of the respiratory mucosa, by surgically creating abone window on the overlying bone and perforating the overlyingrespiratory mucosa from the connective tissue side. The mucosa isperforated by removing the circumscribed bone with the trephine drillalong with the underlying respiratory mucosa attached to the bone. Thedrug delivered into the maxillary sinus can be easily inhaled duringinspiration and can be deposited at the nasal respiratory and olfactorymucosa for further absorption. The drug can also be transported throughthe ostial opening into the middle meatus and onto the nasal respiratorymucosa by muco-ciliary action. This results in increased retention timeof the drug on the mucosal surface and so higher quantity of the drugcan be absorbed into the connective tissue vasculature at therespiratory mucosa and the olfactory mucosa.

Another aspect of the invention provides drug molecules that areengineered for uptake into the goblet cells of the maxillary sinuslining epithelium, from the underlying connective tissue for furthersecretion by the goblet cells along with mucus. This can result in mucusloaded with high concentration of drug molecule for inhalation, whichcan be deposited on the nasal respiratory mucosa and the olfactorymucosa for further absorption.

Another aspect of the invention provides drug molecules that areengineered for affinity to specific sites of the brain. This providesthe required concentration of the drug in the targeted anatomical sitein the brain.

The present invention is illustrated by the accompanying drawings ofvarious embodiments and the detailed description given below. Thedrawings are not to scale. The detailed description and drawings merelydepict exemplary embodiments of the present invention, for explanationand understanding and therefore should not be taken to limit the scopeof the invention to the specific embodiments. Accordingly the scope ofthe invention is to be defined solely by the appended claims andequivalents thereof. It will be appreciated that the components of thepresent invention illustrated in the drawings could be arranged, sizedand designed in a number of different configurations.

Implantable devices and methods for controlled and continuous drugdelivery into the brain by bypassing the blood brain barrier for anumber of medical conditions including Parkinson's, Alzheimer, PainManagement, Epilepsy and Drug Addiction are provided.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the isometric side view, longitudinal sectional view andthree dimensional view of the single unit device.

FIG. 2 shows the isometric side view, longitudinal sectional view andthree dimensional view of a multi-unit device comprising an implant witha central tubular inlet with external threads, a drug delivery assemblyand a retention cap

FIG. 3 shows the isometric side view, longitudinal sectional view andthree dimensional view of a multiunit device comprising an implant witha completely open apex and smooth and rounded walls.

FIG. 4 shows the isometric side view and three dimensional view of amultiunit device comprising an implant with a central tubular inlet withinternal threads at the cervical third and a drug delivery assembly withexternal threads at its cervical part.

FIG. 5 shows the placement and removal tools for use with the device.

FIG. 6 shows the device in the form of a dental implant with an internalspline in the internal wall of body of the implant.

FIG. 7 shows an abutment in the form of a drug delivery systemcomprising a miniaturized internal drug infusion pump and drug reservoirintended for use with the device in the form of a dental implant.

FIG. 8 shows the surgical placement of the device in the form of adental implant in the maxillary alveolar ridge, along with the placementand removal tools.

FIG. 9 shows a mini plate with a central reservoir dial comprising aporous base and with internal threads which is closed with a cap withexternal threads.

FIG. 10 shows a mini plate with a reservoir dial comprising an angulatedupper body for ease of access.

FIG. 11 shows the implant with the porous apical tip located beneath therespiratory mucosa.

FIG. 12 shows the implant with the porous apical tip located above thelevel of the respiratory mucosa.

FIG. 13 shows the implant placed on the anterior wall of the maxillarysinus with the drug delivery tubing extending into the buccal sulcus.The drug delivery tubing is connected to an external drug infusion pumpfor continuous and controlled drug delivery.

FIG. 14 shows a root canal treated tooth whose apex is in contact withthe respiratory mucosa intended for use as a natural drug deliverydevice.

FIG. 15 shows the brain values of dopamine in a rabbit obtained usingHigh performance Liquid Chromatography, after in vivo drug delivery ofdopamine from beneath the respiratory mucosa.

FIG. 16 shows the blood values of dopamine in a rabbit obtained usingHigh performance Liquid Chromatography, after in vivo drug delivery ofdopamine from beneath the respiratory mucosa.

FIG. 17 shows the brain values of lignocaine in a rabbit obtained usingHigh performance Liquid Chromatography, after in vivo drug delivery oflignocaine into the maxillary sinus and on the epithelial surface ofmaxillary sinus mucosa by perforating the lining mucosa from theconnective tissue side.

FIG. 18 The blood values of lignocaine in a rabbit obtained using Highperformance Liquid Chromatography, after in vivo drug delivery oflignocaine into the maxillary sinus and on the epithelial surface ofmaxillary sinus mucosa by perforating the lining mucosa from theconnective tissue side.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description of exemplary embodiments of theinvention makes reference to the accompanying drawings which form a parthereof. The exemplary embodiments of the invention and the method topractice the invention are hereby illustrated in the accompanyingdrawings. Though the exemplary embodiments are described in sufficientdetail to enable those skilled in the art to practice the invention, itshould be appreciated that various changes of the invention may be madewithout departing from the spirit and scope of the present invention.Accordingly the scope of the invention is to be defined solely by theappended claims and equivalents thereof.

It must be appreciated that, in the specification and in the appendedclaims, the singular forms “a,” “an” and “the” refer to plural formsunless the context clearly dictates otherwise. Therefore reference to“the surgical placement” refers to one or more steps and “a therapeuticagent” refers to one or more therapeutic agents.

DEFINITIONS

In describing and claiming the invention, the following terminology willbe used to denote the definitions set forth below

As used herein, “coronal end,” “top end” and “upper end” may be usedinterchangeably to refer to the end of the device that is present abovethe level of the ring and remains above the bone when implanted into thesurgical site.

As used herein “coronal part,” “top part” and “upper part” may be usedinterchangeably to refer to the part of the device that projects abovethe level of the ring and remains above the bone when implanted into thesurgical site.

As used herein, “apical end,” “bottom end” and “lower end” may be usedinterchangeably to refer to the end of the device that is present belowthe level of the ring and remains below the bone, in contact with therespiratory mucosa when implanted into the surgical site.

As used herein “caudal part” “bottom part” and “lower part” may be usedinterchangeably to refer to the part of the device that projects belowthe level of the ring and remains within the bone when implanted intothe surgical site

As used herein “proximal part,” and “mesial part” may be usedinterchangeably to refer to the part which is nearest to the point ofreference or the part that is closest to the median plane of the device.

As used herein “distal part” refers to the part which is away from thepoint of reference or the part that is farther away from the medianplane of the device.

As used herein “cervical third” refers to the upper third part of thelower part of the body of the device that extends from below the levelof the ring, or to the upper third part of the body of the device in theform of a dental implant, wherein the body is divided horizontally byimaginary lines into three equal parts

As used herein “middle third” refers to the middle third part of thelower part of the body of the device that extends from below the levelof the ring, or to the middle third part of the body of the device inthe form of a dental implant, wherein the body is divided horizontallyby imaginary lines into three equal parts

As used herein “apical third” refers to the lower third part of thelower part of the body of the device that extends from below the levelof the ring, or to the lower third part of the body of the device in theform of a dental implant, wherein the body is divided horizontally byimaginary lines into three equal parts.

As used herein, “superior surface” may be used to refer to the uppersurface of a flat or similar shaped embodiment.

As used herein, “inferior surface” may be used to refer to the lowersurface of a flat or similar shaped embodiment.

As used herein, “inlet,” “outlet” and “tubular opening” may be usedinterchangeably to refer to the part of the device that is tubular inshape and is located on the upper part of the device, to which a drugdelivery tubing can be attached for drug delivery into the device.

As used herein, “central lumen,” and “central vent” may be usedinterchangeably to refer to the central hollow space within the body ofthe device, which further opens to the outside through the inlet on thecoronal end and through multiple holes at the apical end.

As used herein, “apical wall” may be used to refer to the wallcomprising the rounded apical end and part of the apical third of thelower part of the device.

As used herein, “slot” and “cleft” may be used interchangeably to referto a vertical opening in the upper end of the inlet intended forplacement of the drug delivery tubing.

As used herein, “drug delivery assembly” refers to a hollow tubingcomprising a vertical part intended for placement into the device and alateral tube extending from the side of the vertical part, wherein themesial end of the tube is intended for placement into the slot of aninlet present on the device.

As used herein, “intra implant part” refers to the vertical part of thedrug delivery assembly intended for placement into the device.

As used herein, “external drug delivery tubing” or “external tubing” maybe used interchangeably to refer to the lateral tube extending from theside of the vertical part intended for placement in the slot of aninlet.

As used herein, “tubing,” and “drug delivery tubing” may be usedinterchangeably to refer to the tube attached to the inlet of thedevice.

As used herein, “intra oral part” refers to the part projecting into orthe part facing the oral cavity.

As used herein, “intra bony part” refers to the part within the bone orbelow the level of the bone.

As used herein “intra-pulpal part” refers to the part that is within thepulp cavity of the tooth.

As used herein, “osseointegration” refers to the process of boneformation around the implant and on the surface of the implant facingthe bone.

As used herein, “abutment,” refers to the removable part that can beplaced into the device which is in the form of a dental implant. It maybe in the form of a drug delivery assembly or a drug reservoir with anin-built drug infusion pump.

As used herein “external involute spline” refers to an involute splinewhose tip surface is located on the external surface of the body of theembodiment.

As used herein “internal involute spline” refers to an involute splinewhose tip surface is located on the internal surface of the body of theembodiment.

As used herein, “claw,” refers to the curved part of the tool that isused for holding a retention cap by its margin.

As used herein, “shaft,” refers to the narrow and straight part of theinstrument, present between the head and the handle.

As used herein, “reservoir,” and “drug reservoir” may be usedinterchangeably to refer to a body comprising a cavity intended to holda therapeutic agent. The therapeutic agent may be in a form in which itcan be easily transferred from the reservoir into the device in acontrolled and continuous manner. As used herein, “external drugreservoir,” refers to a reservoir which is present outside the patient.It is connected to the device in the patient by a tubing whenever drugdelivery is required.

As used herein, “internal drug reservoir,” refers to a reservoir whichis present within the implant. It may be in the form of a cavity withinthe abutment.

As used herein, “infusion pump,” and “drug infusion pump” may be usedinterchangeably to refer to the device that can move the therapeuticagent from the reservoir to the inside of the device in a controlled andcontinuous manner.

As used herein, “therapeutic agent,” and “drug” may be usedinterchangeably to refer to an agent or substance that can produce apharmacologic effect in a human or animal patient when administered intothe patient or that is useful as a diagnostic agent when administered ina patient.

The surgical steps claimed in the methods, can be executed by changingthe order of steps or by avoiding some steps depending on the clinicalrequirements and are not limited to the order presented in the claimsunless otherwise stated. Accordingly the scope of the invention shouldbe determined by the appended claims and their legal equivalents, ratherthan by the descriptions and examples given herein.

Drug Delivery Device

In the preferred embodiment, the single unit implantable device has ahollow cylindrical or tapered body which is closed at both the ends. Thebody comprises a lower part and an upper part, with a barrier ringlocated on the outer surface of the body between the two parts. Theouter surface of the lower part of the implant body that is locatedbelow the circular ring comprises threads from the cervical third to themiddle third. The apical part is smooth and has a plurality of holesthrough the apical wall. The holes may be macro-holes, micro-holes,nano-holes or a combination. A central lumen is present within the body.The central lumen extends from the upper part of the body to the lowerpart of the body and is defined by the surrounding internal wall of theimplant. The central lumen further opens to the external surface at thecoronal part through an inlet and at the apical end through a pluralityof holes at the apical wall of the implant body. This porous apical endis placed in close proximity to the respiratory mucosa. The coronal endof the implant has an external hex for holding and placement of theimplant. A drug delivery inlet is present below the level of theexternal hex on the side of the upper part of the body of the implantfor the attachment of a drug delivery tubing. The inlet may be in theform of an opening with or without internal threads or in the form of atubular projection. The tubular inlet may have a smooth external surfaceor have external or internal threads. The tubular inlet may beperpendicular to the external surface of the body of the implant orangulated towards the coronal end. The inlet opens into the centrallumen present within the body of the device, wherein the central lumenfurther opens to the exterior through the plurality of holes at theapical end. A drug delivery tubing is attached to the inlet and the freeend of the drug delivery tubing is connected to an external drugreservoir attached to a drug infusion pump for controlled drug deliverywhenever required. A circular ring is present below the inlet whichprevents the accidental inward displacement of the implant into themaxillary sinus or into the nasal cavity. The implant is made oftitanium or any other biocompatible material. The tubing is also made ofa resilient and biocompatible material that allows good soft tissueadaptation. The device is manufactured in varying diameters and lengthsto suit the different clinical requirements.

The device delivers one or more drugs in a controlled and continuousmanner, locally at the surgical site in the respiratory mucosal regionwhich can then be transported by neural, vascular, lymphatic orinhalation routes or by a combination of these routes into the brain bybypassing the blood brain barrier.

Exemplary, non-limiting embodiments of the brain drug delivery deviceare illustrated in FIG. 1-18. These figures illustrate variations of thedrug delivery device and the methods for use.

The preferred embodiment is illustrated in FIG. 1. Referring to FIG. 1Fig: A refers to the isometric side view of the single unit device. 101refers to the smooth apical end with a plurality of holes through theapical wall of the body of the implant intended for placement eitherbeneath or above the respiratory mucosa. 102 refers to the threads onthe outer surface of the implant located at the cervical third andmiddle third of the lower part of the implant body. 103 refers to thebarrier ring intended for preventing the unintentional inwarddisplacement of the implant into the maxillary sinus or the nasalcavity. 104 refers to the inlet intended for connection to the drugdelivery tubing. 105 refers to the drug delivery tubing. The end one ofthe tubing is either friction fit or threaded onto or into the inlet.The end two of the tubing is free and has a nozzle at the free end. 106refers to the nozzle at the free end of the drug delivery tubing whichmay be placed in the buccal sulcus overlying the mucosa, in the buccalgingival sulcus or in the palatal gingival sulcus. The nozzle at thefree end of the tubing can be closed with a temporary cap. 107 refers tothe external hex on the head part of the implant which is intended tofit into a placement tool and thereby assist in holding and placement ofthe implant into the surgical site. Fig: B refers to the longitudinalsectional view of the implant. 101 refers to the smooth and roundedapical end of the implant with a plurality of holes. 102 refers to thethreads on the outer surface of lower part of the implant. 103 refers tothe barrier ring. 104 refers to the inlet to which the drug deliverytubing is connected. 107 refers to the external hex. 108 refers to thecentral lumen. 109 refers to the external threads on the inlet. Fig: Crefers to the 3D rendered view of Fig: A.

An alternative embodiment is illustrated in FIG. 2. The alternativeembodiment is a multiunit device comprising an inlet located centrallyat the coronal end of the implant body. The inlet further comprisesexternal threads at its cervical third and a vertical slot extendingfrom its tip to its middle third. The drug delivery assembly comprisesan intra implant part and an external drug delivery tubing. The intraimplant part is tapering in shape and comprises a central lumen withinthe body and a plurality of holes through the wall at the apical end.The drug delivery tubing is tubular in shape comprising a central lumenand is attached to the side of the intra-implant part. The central lumenof the intra implant part and the drug delivery tubing are continuouswith each other. When the intra-implant part is pushed into centrallumen within the implant, the proximal end of the drug delivery tubingis also slid across the vertical slot on the side of the inlet. A cap isthreaded onto the external threads on the inlet. The cap covers the slotand extends till the surface of the tubing. The cap retains theintra-implant part within the implant. An external hex is present belowthe inlet that helps in holding and placing the implant. A circular ringis present below the external hex which prevents the accidental inwarddisplacement of the implant into the maxillary sinus or into the nasalcavity. Referring to FIG. 2, Fig: A refers to an isometric side view ofa multi-unit drug delivery device. 201 refers to the smooth apical endwith a plurality of holes through the apical wall of the body of theimplant intended for placement either beneath or above the respiratorymucosa. 202 refers to the threads on the outer surface of the implantlocated at the cervical third and middle third of the lower part of theimplant body. 203. Refers to the barrier ring. 204. Refers to theexternal hex. 205 Refers to the outer threads on the tubular inlet. 206Refers to the intra implant part of the drug delivery assembly. 207Refers to the external tubing of the drug delivery assembly. 208 Refersto the nozzle at the free end of the drug delivery tubing 209. Refers tothe cap with internal threads that can be threaded onto the drugdelivery inlet. It retains the intra implant part within the implant.210 refers to the plurality of holes at the apex of the intra implantpart of the drug delivery assembly. Fig: B is a longitudinal sectionalview of the lower part of the implant body and the components comprisedwithin. 201. Refers to the porous apical end. 202. Refers to theexternal threads 203. Refers to the barrier ring. 204. Refers to theexternal hex. 206. Refers to the intra implant part of the drug deliveryassembly with a central lumen and porous tip. 207. Refers to theexternal tubing of the drug delivery assembly. 208. Refers to the nozzleat the free end of the drug delivery tubing. 209. Refers to the cap withinternal threads that is threaded onto the drug delivery inlet. Itretains the intra implant part within the implant. 210. Refers to theporous apical end of the intra implant part of the drug deliveryassembly within the implant. Fig: C is a 3D rendered view of Fig A. Fig:D is a 3D rendered view of Fig B.

Another preferred embodiment is illustrated in FIG. 3. The alternativeembodiment is a multiunit implant assembly comprising a completely openapex with beveled and outwardly flaring internal walls and smooth androunded margins and an inlet located centrally at the coronal end of theimplant body. The inlet further comprises external threads at itscervical third and a vertical slot extending from its tip to its middlethird. The drug delivery assembly comprises an intra implant part and anexternal drug delivery tubing. The intra implant part is tapering inshape and comprises a central lumen within the body and a plurality ofholes through the wall at the apical end. The drug delivery tubing istubular in shape comprising a central lumen and is attached to the sideof the intra-implant part. The central lumen of the intra implant partand the drug delivery tubing are continuous with each other. When theintra-implant part is pushed into central lumen within the implant, theproximal end of the drug delivery tubing is also slid across thevertical slot on the side of the inlet. The tip of the intra-implantpart is positioned at the apical opening of the central lumen which islocated below the level of the outer rounded apical margins. A cap isthreaded onto the external threads on the inlet. The cap covers the slotand extends till the surface of the tubing. The cap retains theintra-implant part within the implant. An external hex is present belowthe inlet that helps in holding and placing the implant. A circular ringis present below the external hex which prevents the accidental inwarddisplacement of the implant into the maxillary sinus or into the nasalcavity. Referring to FIG. 3, Fig: A refers to an isometric side view ofa multi-unit implant with a completely open apex. 301. Refers to thecompletely open apex with smooth and rounded margins. 302. Refers to theexternal threads 303. Refers to the barrier ring. 304. Refers to theexternal hex. 305 Refers to the outer threads on the tubular inlet. 306Refers to the intra implant part of the drug delivery assembly. 307Refers to the external tubing of the drug delivery assembly. 308 Refersto the nozzle at the free tip of the drug delivery tubing. 309. Refersto the cap with internal threads that can be threaded onto the drugdelivery inlet. It retains the drug delivery assembly within theimplant. 310. Refers to the plurality of holes at the apex of the intraimplant part of the drug delivery assembly. Fig: B is a longitudinalsectional view of the lower part of the implant body and the componentscomprised within. 301. Refers to the completely open apex with smoothand rounded margins. 302. Refers to the external threads 303. Refers tothe barrier ring. 304. Refers to the external hex. 306. Refers to theintra implant part of the drug delivery assembly with a central lumenand porous tip which is placed short of the apical margin. 307. Refersto the external tubing of the drug delivery assembly. 308. Refers to thenozzle at the free end of the drug delivery tubing. 309. Refers to thecap with internal threads that is threaded onto the drug delivery inlet.It retains the intra implant part within the implant. 310. Refers to theporous apical end of the intra implant part of the drug deliveryassembly within the implant. Fig: C is a 3D rendered view of Fig A. Fig:D is a 3D rendered view of Fig B.

An alternative embodiment is illustrated in FIG. 4. The alternativeembodiment comprises a multi-unit implantable device with a body in theform of a hollow cylindrical tube with the upper end open and the apicalend closed. The apical end is rounded with a plurality of holes throughthe apical wall and the upper end comprises a drug delivery inlet withinternal threads. The external surface of the upper part of the bodyfurther comprises an external hex below the drug delivery inlet and abarrier ring below the external hex. A central lumen is present withinthe body comprising tapering walls defined by the internal wall of thebody of the device. The central lumen communicates with the exteriorthrough an inlet at the upper end and the plurality of holes in the wallat the apical end. Threads are present on the external surface of thelower part of the body at the cervical third, below the level of thering. An inlet is located at the upper end of the device, comprisinginternal threads at its cervical third. An external hex is located belowthe inlet at the upper part of the device. A circular ring is locatedbelow the level of the tubular inlet and comprises a convex and smoothupper surface and a flat and smooth undersurface facing the bone. Thedrug delivery assembly comprises a tapered intra-implant part withexternal threads at its upper part and an external drug delivery tubingattached to the upper end of the intra-implant part. The intra-implantpart is threaded into the inlet wherein the external walls of the intraimplant part fit tightly to the internal walls of the implant except atthe apical third. A space is present at the apical third between theinternal wall of the implant and the external wall of the intra-implantpart, wherein the drug is initially delivered. The drug further movesout through the holes at the apical end of the implant. Referring toFIG. 4, Fig: A refers to an isometric side view of a multi-unit implantwith the tubular central outlet with internal threads at the top orcoronal aspect. 401. Refers to the porous apical end. 402. Refers to theexternal threads 403. Refers to the barrier ring. 404. Refers to theexternal hex. 405 Refers to the tubular outlet with internal threads.406 Refers to the intra implant part of the drug delivery assembly. 407Refers to the external tubing of the drug delivery assembly. 408 Refersto the nozzle at the free tip of the drug delivery tubing. 409 refers tothe external hex on the upper end of the intra implant part 410. Refersto the porous apical end of the intra implant part of the drug deliveryassembly within the implant. 411. Refers to the external threads on theintra-implant part of the drug delivery assembly. The intra-implant partis threaded into the inlet. Fig: B is a 3D rendered view of Fig A.

The drug delivery device is held and placed in the surgical site usingspecialized instruments because of the limited anatomical spaceavailable for use and the need for sterilized instruments. Theinstruments may be hand held or rotary. The instruments may be in theform of ratchets or spanners of varying sizes and length. Theinstruments basically consist of a head and a handle. The head adapts tothe external hex present on the implant or on the retention cap. Thehead may be of varying diameters. The handle may be of varying lengthsand angulations. The handle may be hand held and used or may be attachedto a low speed rotary handpiece. The preferred embodiments areillustrated in FIG. 5. Referring to FIG. 5, 5X refers to the externalhex on the implant Fig: A Refers to the spanner for placement andremoval. 501. Refers to the head which adapts to the external hex on theimplant. 502. Refers to the handle. Fig: B Refers to an angulatedspanner. 503. Refers to the head which adapts to the external hex on theimplant. 504. Refers to the angulated handle. Fig: C refers to the handheld ratchet. 505. Refers to the head which adapts to the external hexon the implant. 506. Refers to the handle. Fig: D refers to an angulatedhand held ratchet. 507. Refers to the head which adapts to the externalhex on the implant. 508. Refers to the angulated handle. Fig: E refersto a hand held rotating placement and removal tool. 509. Refers to thehead which adapts to the external hex on the implant 510. Refers to therotating finger rest. Fig: F refers to a rotary placement and removaltool. 511. Refers to the head which adapts to the external hex on theimplant. 512. Refers to the shank that can fit into the rotaryinstrument.

Another preferred embodiment is illustrated in FIG. 6. In thisembodiment, the device is in the form of a hollow dental implant made oftitanium alloy or any other biocompatible material with externalthreads. The implant has micro holes at the apical part of the implantbody. The holes connect the central lumen defined by the internalsurface of the implant with the nasal respiratory mucosa or themaxillary sinus lining mucosa. The implant has an internal involutespline within the implant body. The implant has internal threads at thecervical end. The disposable abutment made of a bio-compatible materialhas a body comprising an intra-oral part and an intra-implant part witha barrier ring on the external surface between the two parts. Theexternal surface of the intra-implant part of the abutment has anexternal involute spline and a micro-porous apical end. The abutmentfurther comprises a central lumen that communicates to the exteriorthrough a drug delivery tubing at the coronal end of the intraoral partof the abutment. The external involute spline of the abutment fits intointernal involute spline of the dental implant. The plurality of holesat the apical tip of the abutment is in alignment and in line with theplurality of holes at the apex of the implant. A cervical ringcomprising an external hex with a central hole at the upper part outerand external threads at the lower part is slid from the top of theabutment and threaded into the inner threads at the cervical part of theimplant. The inner aspect of the cervical ring adapts closely andtightly to the outer surface of the abutment to form a tight junctionwithout any micro-leakage. The drug is delivered into the central lumenthrough the drug delivery tubing extending from the coronal end of theintraoral part of the abutment. In an alternative embodiment, thecervical ring is of variable heights depending on the soft tissuerequirements and is well adapted to the wall of the abutment ontightening. Fig: A refers to the isometric side view of the dentalimplant 601 refers to the apical pores in the implant. 602 refers to theexternal threads on the implant. 603 refers to the smooth cervical end.604 refers to the apical holes of the abutment. 605 refers to theexternal involute spline on the abutment. 606 refers to the barrierring. 607 refers to the intra-oral part of the abutment. 608 refers tothe external threads on the cervical ring. 609 refers to the cervicalring. 610 refers to the external hex on the cervical ring. 611 refers tothe drug delivery tubing. 612 refers to the nozzle at the distal freeend of the tubing. Fig: B refers to the 3 D rendered view of Fig A. Fig:C refers to the isometric side view of the dental implant and theplacement tool. 601 refers to the apical holes in the implant. 602refers to the external threads on the implant. 603 refers to the smoothcervical end. 613 refers to the external involute spline on theplacement tool. 614 refers to the barrier ring on the placement tool.615 refers to the shank of the placement tool. 616 refers to theexternal hex on the hand held placement tool. Fig: D refers to the 3 Drendered view of Fig C. 613 refers to the external involute spline onthe placement tool. 614 refers to the barrier ring on the placementtool. 615 refers to the shank of the placement tool. 616 refers to theexternal hex on the hand held placement tool. 617 refers to the internalcervical threads within the implant. 618 refers to the internal splinewithin the implant. 619 refers to the central lumen within the implant.

The alternative embodiments of the abutment, intended for use with thedevice in the form of a dental implant is illustrated in FIG. 7.Referring to FIG. 7, Fig A is a 3D rendered view of the abutment. 701refers to the inlet on the coronal tip of the abutment intended forattaching a drug delivery tubing. 702 refers to the intra-oral part ofthe abutment. 703 refers to the barrier ring. 704 refers to the externalinvolute spline. 705 refers to the apical holes. Fig B is thelongitudinal section of Fig A. 706 refers to the central lumen withinthe body of the implant. In an alternative embodiment, speciallydesigned abutments in the form of drug reservoirs comprising in-built,miniature, osmotically or electronically controlled infusion pumps areused for drug delivery with the device. Fig C refers to the abutmentcomprising a drug reservoir in the lower part, an osmotic compartmentholding the osmotic agent in the middle part and a semipermeablemembrane separating the middle part from the upper part. The upper parthas a space to hold an injected osmotic solvent. When the solvent isinjected into the upper part, the solvent moves across the semipermeablemembrane into the osmotic compartment and causes it to expand, therebypushing the drug out from the reservoir at a predetermined rate throughthe apical holes. 701 refers to the inlet on the coronal tip of theabutment intended for delivering the osmotic solvent. 702 refers to theintra-oral part of the abutment that holds the osmotic solvent. 703refers to the barrier ring. 705 refers to the apical holes. 707 refersto the semipermeable membrane separating the middle part and the upperpart of the abutment. 708 refers to the osmotic compartment. 709 refersto the drug reservoir. Fig D refers to the abutment comprising a drugreservoir in the lower part and an electronic drug infusion pump in theupper part. 702 refers to the intra-oral part of the abutment that holdsthe electronic drug infusion pump. 703 refers to the barrier ring. 705refers to the apical holes. 709 refers to the drug reservoir. 710 refersto the electronic drug infusion pump In an alternative embodiment, theabutment may be used as a drug reservoir for continuous drug delivery,by modifying the size of the plurality of holes at the apical part ofthe abutment into holes that equal the size of the drug molecule. Thisresults in delivery of the drug molecules at a pre-determined rate. FigE refers to the abutment used as an internal drug reservoir. 702 refersto the intra-oral part of the abutment. 703 refers to the barrier ring.705 refers to the apical holes. 709 refers to the drug reservoircompartment extending from the lower to upper part of the abutment. Inan alternative embodiment, the intra oral part of the abutment may beangulated above the level of the cervical ring. In another alternativeembodiment, the inlet on the abutment may be in the form of an openingwith internal threads and located on the side of the intra-oral part.

In the case of preparing the surgical site on the maxillary alveolarprocess, an osteotomy dental drill of appropriate length and diameter isused. The osteotomy is stopped short by 1 mm of the maxillary sinuslining mucosa or the nasal respiratory mucosa. The apical 1 mm of boneis gently broken with a bone compression tool or with an elevator bygentle tapping. Care is taken not to tear the respiratory mucosa in thenasal or the maxillary sinus region. Placement of the device in the formof a dental implant into the alveolar bone using the requiredinstruments is illustrated in FIG. 8. 801. Refers to the ratchet forholding the bone compression tool. 802 refers to the bone compressiontool being used for enlarging the soft osteotomy site and for breakingthe apical wall to access the respiratory mucosa. 803 refers to theosteotomy site in the maxillary region underlying the respiratorymucosa. 804 refers the porous apical end of the implant. 805 refers tothe body of the implant being placed into the osteotomy site. 806 refersto the placement tool used for placing the implant into the osteotomy.807 refers to the ratchet for holding the placement tool. 808 shows theabutment placed into the implant. 809 shows the cervical retention capcomprising a central hole being placed across the intra oral part of theabutment. The cap further comprises a plurality of holes at theperiphery on the superior surface of the upper part. 810 refers to theprojections at the tip of the placement tool intended for placement intothe holes on the superior surface of the upper part of the ring. 811refers to the body of the placement tool. 812 refers to the rotating endintended for finger rest on the placement tool. 813 refers to the clawof the removal tool. 814 refers to the handle of the removal tool. 815Refers to the vertically moveable shank of the device. 816 refers to therotating end intended for finger rest on the removal tool. 817 refers tothe inlet in the upper end of the abutment. 818 refers to the maxillarysinus or the nasal cavity comprising respiratory lining mucosa.

Another preferred embodiment is illustrated in FIG. 9. In the preferredembodiment, an implantable single unit drug delivery device is providedthat comprises a mini plate with a central drug reservoir dial whereinthe reservoir has a porous base with parallel walls, external orinternal threads at the top part of the dial wall and a cap withinternal or external threads made of a resilient, biocompatible materialthat self-seals whenever penetrated by a needle are used for drugdelivery. The porous base of the drug reservoir dial comprises macroholes, micro holes or nano holes and is intended for placement beneathor above the respiratory mucosa. The drug is delivered into the drugreservoir dial using a needle that may be connected to a syringe or anexternal drug infusion pump. The needle penetrates the cap and depositsthe drug into the drug reservoir dial. Alternatively a reservoircontaining a drug with a rate limiting membrane at the base can also beplaced into the dial. The drug reaches the respiratory mucosa throughthe holes in the drug reservoir dial base. The mini plate is secured tothe bone by screws. Referring to FIG. 9, Fig A shows the top view of amini plate with a central micro-porous or nanoporous drug reservoir dialand straight limbs. 901 refers to the straight limb with screw holes.902 refers to the central drug reservoir dial with internal or externalthreads. A cap is threaded onto the threads 903 refers to themicro-porous or nanoporous base of the drug reservoir dial. The drug isdeposited into the dial. Fig B shows a top view of the mini plate with acentral micro-porous or nanoporous drug reservoir dial and a left Lshaped limb. 901 refers to the straight limb with screw holes. 902refers to the central drug reservoir dial with internal or externalthreads. A cap is threaded onto the threads 903 refers to themicro-porous or nanoporous base of the drug reservoir dial. The drug isdeposited into the dial. 904 refers to the left L shaped limb with screwholes. Fig C shows the top view of a mini plate with a centralmicro-porous or nanoporous drug reservoir dial and a right L shapedlimb. 901 refers to the straight limb with screw holes. 902 refers tothe central drug reservoir dial with internal or external threads. A capis threaded onto the threads 903 refers to the micro-porous ornanoporous base of the drug reservoir dial. The drug is deposited intothe dial. 904 refers to the right L shaped limb with screw holes. Fig Dshows the cap made of a resilient, biocompatible material thatself-seals whenever penetrated by a needle. 905 refers to the holes usedfor holding the cap while threading it onto the reservoir dial. 906refers to the self-sealing part of the cap into which needles can beinserted. 907 refers to the threads on the cap. The threads can beexternal or internal.

An alternative embodiment comprises a mini plate with a centralreservoir dial wherein the reservoir has a porous base with angulatedwalls and a cap made of a resilient, biocompatible material thatself-seals whenever penetrated by a needle. The upper end of the cap hasan external hex and the lower part of the cap has internal or externalthreads. The angulation helps in ease of placing the needle tip into thereservoir for drug delivery from the oral cavity, when the mini plate islocated on concave surfaces like the anterior wall of the maxillarysinus. The alternative embodiment is herein illustrated in FIG. 10.Referring to FIG. 10, Fig A shows the side view of a mini plate with acentral drug reservoir dial, comprising a hollow body with an upperangulated part and a lower straight part, a straight limb and an Lshaped limb between the two parts of the dial. 1001 refers to thestraight limb with screw holes. 1002 refers to the central drugreservoir dial with angulated walls comprising internal or externalthreads at the upper part. 1003 refers to the cap that is threaded ontothe threads 1004 refers to the straight part of the reservoir dialcomprising a micro-porous or nanoporous base intended for placementbelow the respiratory mucosa. 1006 refers to the retention screw. Fig Bshows the top view of a mini plate with a central drug reservoir dial,comprising a hollow body with an upper angulated part and a lowerstraight part with straight limbs between the two parts of the dial.1001 refers to the straight limb with screw holes. 1002 refers to thecentral drug reservoir dial with angulated walls comprising internal orexternal threads at the upper part. 1003 refers to the cap that isthreaded onto the threads. 1006 refers to the retention screw. Fig C andD show the top view of a mini plate with a central angulated drugreservoir dial comprising a straight limb and an L shaped limb. 1001refers to the straight limb with screw holes. 1002 refers to the centraldrug reservoir dial with angulated walls comprising internal or externalthreads at the upper part. 1003 refers to the cap that is threaded ontothe threads 1005 refers to the L shaped limb. It may point to the rightor to the left. 1006 refers to the retention screw.

II. Method for Drug Delivery A. Surgical Preparation of the ImplantationSite

A full thickness buccal or palatal mucosal flap is elevated. A bonewindow is marked on the bone overlying the respiratory mucosa using abone trephine drill of appropriate length and diameter. The bone windowcan be surgically prepared at a number of anatomical sites which alsoinclude the hard palate forming the floor of the maxillary sinus or thenasal cavity, anterior wall of the maxillary sinus or the zygomaticprocess of the maxilla. The bone window can be gently pried out with therotating trephine drill without damaging the underlying respiratorymucosa. Alternatively the circumscribed bone can be removed gentlywithout damaging the underlying mucosa using a piezo instrument. Therespiratory mucosa is gently released and elevated from the surroundingbone margins without tearing the respiratory mucosa by using a softtissue elevator of appropriate diameter.

In the case of preparing the surgical site on the maxillary alveolarprocess, an osteotomy dental drill of appropriate length and diameter isused. The osteotomy is stopped short by 1 mm of the maxillary sinuslining mucosa or the nasal respiratory mucosa. The apical 1 mm of boneis gently broken with a bone compression tool or with an elevator bygentle tapping. Care is taken not to tear the respiratory mucosa in thenasal or the maxillary sinus region.

Surgical Placement of the Implant

A ratchet or implant placement tool which fits into the external hex onthe implant is used to hold and place the implant. The implant of thecorrect diameter and length is gently threaded into the preparedosteotomy site using a hand held ratchet or a rotary placement tool.Alternatively the implant can be gently press fit into the osteotomyhole. The barrier ring prevents the accidental displacement of theimplant into the maxillary sinus or the nasal cavity. The respiratorylining mucosa is further elevated by the smooth apical end of theimplant. The porous apical part of the hollow implant is thus in contactwith the connective tissue base of the respiratory lining mucosa. Thedrug delivery assembly or the delivery tubing is attached to the implantat the drug delivery inlet. The elevated soft tissue flap is placed backin position and the entire assembly is allowed to heal. The outer end ofthe drug delivery tubing can be placed in the buccal sulcus overlyingthe oral mucosa, in the buccal gingival sulcus or in the palatalgingival sulcus. The nozzle at the free end of the tubing can be closedwith a temporary cap. Whenever needed, the tubing can be attached to anexternal drug infusion pump for controlled drug delivery.

B. Location of the Apical Porous Tip of the Device with Respect to theRespiratory Mucosa

1. The porous apical tip of the implant may be surgically placed beneaththe intact respiratory mucosa at a number of anatomical sites which alsoinclude the maxillary sinus, hard palate forming the floor of the nasalcavity or maxillary sinus, the zygomatic process of the maxilla or thenasopalatine foramen. The drug can be delivered beneath the intactrespiratory mucosa which is the connective tissue side of therespiratory mucosa in a continuous and controlled manner through theplurality of holes through the apical wall of the hollow implant, byconnecting the drug delivery tubing of the implant to an external drugreservoir attached to a drug infusion pump. The drug distributes intothe brain by bypassing the blood brain barrier from the delivery sitewithout increasing the concentration of the drug in the peripheralcirculation. The drug delivery route into the brain may either bethrough the neural, lymphatic or the vascular route or a combination ofall the routes. This is useful for drugs which need to be given inprecise concentrations and in low volumes. Drugs can thus be deliveredinto the brain by bypassing the blood brain barrier.

Referring to FIG. 11: Fig: A refers to the isometric view of themaxillofacial implantable drug delivery device placed beneath the nasalrespiratory mucosa or the maxillary sinus lining mucosa. 1101 refers tothe respiratory mucosal lining. 1102 refers to the smooth porous apicalend of the implant. 1103 refers to the drug delivered under therespiratory mucosa. 1104 refers to the surrounding alveolar bone. 1105refers to the overlying oral mucosa. 1106 refers to the threads on theouter surface of the implant. 1107 refers to the barrier ring. 1108refers to the drug delivery tubing. 1109 refers to the nozzle at thefree tip of the drug delivery tubing. 1110 refers to the external hex.Fig B is a 3D rendered view of Fig A.

2. The porous apical tip of the implant may be also placed into themaxillary sinus and above the level of respiratory mucosa by perforatingthe respiratory mucosa from underneath or the connective tissue side.The drug can be delivered from an external drug reservoir into themaxillary sinus and onto the epithelial surface of the mucosal lining,in a continuous and controlled manner through the plurality of holes atthe apical wall of the implant by using an external drug infusion pump.The drug can then be easily inhaled during inspiration since the air inthe normal maxillary sinus empties during routine inspiration and fillswith air during expiration. The inhaled drug can be further deposited onthe nasal respiratory and olfactory mucosa for absorption. Moreoverbecause of the muco-ciliary action, the drug can also be transportedfrom the maxillary sinus onto the nasal respiratory mucosa through theostial opening at the middle meatus. This drug can be further be inhaledto reach the olfactory mucosa also. Because of the extra time taken formuco ciliary clearance from the maxillary sinus to the nasal respiratorymucosa, the retention time of the drug on the mucosal surface isincreased, resulting in absorption of higher quantity of the drug. Thisroute is useful for drug formulations that are inhalable and can begiven in larger volumes.

Referring to FIG. 12: Fig: A refers to the isometric view of themaxillofacial implantable drug delivery device placed into the maxillarysinus with the tip above the level of the lining respiratory mucosa.1201 refers to the respiratory mucosal lining. 1202 refers to the smoothmicroporous apical end of the implant. 1203 refers to the drug deliveredabove the respiratory mucosa. 1204 refers to the surrounding alveolarbone. 1205 refers to the overlying oral mucosa. 1206 refers to thethreads on the outer surface of the implant. 1207 refers to the barrierring. 1208 refers to the drug delivery tubing. 1209 refers to the nozzleat the free tip of the drug delivery tubing. 1210 refers to the externalhex. Fig B is a 3D rendered view of Fig A.

D. Controlled and Continuous Drug Delivery.

The nozzle at the free end of the drug delivery tubing which is locatedover the oral mucosa in the buccal sulcus, at the buccal gingival sulcusor the palatal gingival sulcus is connected to an external reservoirattached to a drug infusion pump. The external electronically controlledinfusion pump provides a continuous and controlled rate of delivery ofdrugs at the range of milliliters, microliters or nanoliters into theimplant. This is essential to provide drug delivery without traumatizingthe respiratory mucosa, to prevent backflow of drug from the device dueto high rate of drug inflow and to prevent leakage or overflow of thedrug across the mucosal delivery site due to high rate and large volumeof drug delivery at the implant-mucosal interface. The preferred methodis illustrated in FIG. 13. Fig A shows the device placed at the anteriorwall of the maxillary sinus. 1301 refers to the barrier ring. 1302refers to the external hex. 1303 refers to the drug delivery tubing. FigB shows the device connected to an external drug reservoir attached to adrug infusion pump. 1304 refers to the external drug infusion pumpcomprising a drug reservoir that is attached to the free end of the drugdelivery tubing of the device.

Alternatively, as in FIGS. 7: C and D, an abutment comprising aninternal drug reservoir at the intra-implant part which is controlled bya miniature drug infusion pump located in the intra-oral part, can beused with the device in the form of a dental implant for controlled andcontinuous drug delivery. This system can be used when the device isintended for placement into the alveolar ridge, small quantity of drughas to be delivered over a period of time, and access is available tochange the abutment after the drug is delivered. Alternatively as inFIG. 7: E, the abutment may be used as a drug reservoir for continuousdrug delivery, by modifying the plurality of holes at the apical part ofthe abutment into holes that equal the size of the drug molecule. Thisresults in delivery of the drug molecules at a pre-determined rate.

Optional Procedures for Different Clinical Situations

In case of emergency, the drug can be directly delivered beneath therespiratory mucosa on the connective tissue side using the drug deliveryassembly which is connected to an external drug reservoir attached to adrug infusion pump.

A biocompatible cement can be applied to the undersurface of the barrierring of the implant to fix the barrier ring to the underlying bone. Thisretains the implant in position and prevents movement during immediatedrug delivery.

The barrier ring of the implant may also be provided with screw holes atthe periphery or with retentive limbs containing screw holes. Miniscrews can be placed in the holes if additional retention is required.

In another form of the embodiment as illustrated in FIG. 14, a rootcanal treated tooth whose apex is in contact with the respiratory mucosais used as a natural drug delivery device. After biomechanicalpreparation of the pulp cavity of the tooth till the apex, the coronalpart of the tooth is prepared for the crown. An additional vertical slotis prepared on the tooth extending from the occlusal surface to themiddle part of buccal or palatal wall. A crown is made using abiocompatible material. A cylindrical tube open at both the ends isincluded as a part in the crown at the middle third of the palatal orbuccal wall, further wherein the intra oral end of the tube that opensinto the oral cavity at the buccal or palatal side has internal threadsand the intra pulpal end of the tube that opens into the pulp chamber issmooth with a straight or an apically curved end. The part of the crownwith the cylindrical tube is slid into the vertical slot in the crown ofthe tooth during the cementation of the crown. A drug delivery tubing isthreaded into the open end of the inlet tube on the buccal or palatalside for drug delivery. The opening is closed with a disposable cap whennot in use. FIG. 14 shows an upper molar with its root tips in closeproximity to the overlying maxillary sinus lining mucosa. 1401 refers tothe maxillary sinus lining. 1402 refers to the opening at the root apex.1403 refers to the enlarged and debrided pulp canal. 1404 refers to thealveolar bone. 1405 refers to the gingiva. 1406 refers to the pulpchamber. 1407 refers to the vertical slot on the buccal wall. 1408refers to the tooth prepared for receiving the prosthetic crown. 1409refers to the drug delivery inlet on the prosthetic crown. 1410 refersto the prosthetic crown.

In cases where the device in the form of a dental implant which isplaced into the alveolar ridge, a dental crown with a buccal or palatalinlet is used with an abutment that also has a corresponding inletopening on the side of the intra-oral part. Drug is delivered into theimplant through the inlet in the abutment which in turn is accessedthrough the inlet in the buccal or palatal wall of the crown. The inletopening in the crown is closed with a screw when not used for drugdelivery.

In cases where mini plates with drug reservoir dials are used, a fullthickness mucosal flap is elevated. Appropriate diameter of bone isremoved with a bur or a piezo instrument, without damaging the overlyingrespiratory epithelium. The dial is placed into the osteotomy with itsporous base in close proximity to the respiratory mucosa. The mini plateis fixed to the bone by mini screws. The top of the dial is closed witha threaded cap which is biocompatible and self-seals when penetrated bya needle. The flap is replaced over the reservoir and allowed to heal.Drug can be injected into the reservoir dial space using a needle fromthe overlying anaesthetized mucosa whenever needed.

E. Applications of the Delivery Device

The brain drug delivery implant can be used for a single dose of drugdelivery and then removed or can be retained at the anatomical site fora longer period of time if multiple doses of the drug is required. Asingle drug or a combination of drugs can be delivered. Stem cells andsmall interference RNAs can also be delivered into the brain using thisdevice and the methods.

Hence this device and the methods can be used to deliver the drugs intothe brain bypassing the blood brain barrier in patients with Alzheimer,Parkinson, Drug addiction, Cancer, White matter disease, Painmanagement, Brain infections, Psychiatric conditions and a myriad ofother relevant medical conditions.

The brain drug delivery device and the methods of drug delivery thereofwill be further understood by reference to the following non-limitingexamples.

Example 1 Controlled and Continuous Delivery of Drugs Beneath theRespiratory Mucosa

The device was surgically placed in a rabbit in the maxillary sinusregion by removing the bone overlying the respiratory mucosa. The tip ofthe device was placed beneath the maxillary sinus lining mucosa in closeproximity to the connective tissue side of the mucosa. Dopamine wasinfused in a controlled and continuous manner under the maxillary sinusmucosa of the rabbit for twenty minutes at the rate of 1 milliliter perhour by using an external drug infusion pump connected to the implanteddevice. Whole body perfusion was done using a peristaltic pump with warmphysiological saline for 20 minutes at a controlled rate. The perfusedbrain was then resected at the end one hour from the start of theprocedure. Brain samples from different parts of the brain was analyzedusing High Performance Liquid Chromatography. There was an increasedconcentration of dopamine in all parts of the brain except diencephalonwhen compared with the normal. Thus the drug had bypassed the bloodbrain barrier. FIG. 15 refers to the comparative brain values ofdopamine using High Performance Liquid Chromatography, between thecontrol and the rabbit in which dopamine was delivered in vivo in acontinuous and controlled manner under the maxillary sinus mucosa usingthe drug delivery system. During the procedure, a blood sample wascollected before drug delivery. Three blood samples were then collectedat intervals of 10, 20 and 30 minutes respectively following start ofdrug delivery. The samples were analyzed using High Performance LiquidChromatography. The blood values dipped during drug delivery at the 10and 20 minute interval. The drug delivery was stopped at the twentiethminute. Subsequently the blood value peaked again at the 30 minuteinterval. FIG. 16 refers to blood values of dopamine in the rabbit afterin vivo delivery of dopamine under the maxillary sinus mucosa using thedevice. This shows that dopamine delivered using the device had reachedthe brain by bypassing the blood brain barrier and may have effected alow dopamine peripheral response by a feedback mechanism in the brainduring drug delivery. The peripheral value would have increased afterthe central negative feedback control had ceased once the drug deliverywas stopped. Moreover there was no increase of the drug in peripheralcirculation during drug delivery.

Example 2 Controlled and Continuous Delivery of Drugs Above theRespiratory Mucosa

The device was placed into the maxillary sinus of a rabbit byperforating the maxillary sinus mucosa from the connective tissue sideand placing the implant tip into the sinus cavity and above theepithelial layer. Lignocaine was infused in a controlled and continuousmanner for twenty minutes at the rate of 1.5 milliliter per hour byusing an external drug infusion pump connected to the implanted device.Whole body perfusion was done using a peristaltic pump with warmphysiological saline for 20 minutes at a controlled rate. The perfusedbrain was then resected at the end one hour from the start of theprocedure. Brain samples from different parts of the brain was analyzedusing High Performance Liquid Chromatography. There was an increasedconcentration of Lignocaine in some parts of the brain as shown in theFIG. 17. Thus the drug had bypassed the blood brain barrier. But thetissue distribution was lesser and the tissue concentration was lesswhen compared to a similar volume of the drug delivered beneath therespiratory mucosa. During the procedure, a blood sample was collectedbefore drug delivery. Three blood samples was then collected atintervals of 10, 20 and 30 minutes respectively following start of drugdelivery. The samples were analyzed using High Performance LiquidChromatography. There was no drug in the peripheral circulation. FIG. 18refers to the blood values of Lignocaine in the rabbit after the in vivodelivery of Lignocaine into the maxillary sinus cavity and onto theepithelial surface of the maxillary sinus mucosa using the device

The above mentioned methods and device are only illustrative of theprinciple of the present invention. Modifications and variations of themethods and devices including but not limited to, variations in size,materials, shape, assembly, function, use and mode of operation will beobvious to those of ordinary skill in the art from the foregoingdetailed description. Such modifications and variations made withoutdeparting from the spirit and scope of the invention set forth hereinare intended to come within the scope of the appended claims.

We claim:
 1. A drug delivery system for delivering drugs into the brain,by bypassing the blood brain barrier comprising an implantable hollowdevice made of titanium or any other biocompatible material, intendedfor placement into the bone overlying the respiratory mucosa of themaxillary sinus and the nasal cavity. a drug delivery assembly made of abiocompatible material intended for transferring therapeutic agents froman external drug reservoir into the central lumen of the hollowimplantable device. a drug infusion pump intended for providingcontinuous and controlled drug delivery from an external drug reservoirinto the central lumen of the implantable hollow device a therapeuticagent intended for delivery into the brain an instrument kit for placingand removing the implantable device and the accompanying components. 2.The device of claim 1, wherein the device comprises a body in the formof a hollow cylindrical tube with both the ends closed, wherein theapical end is rounded with a plurality of holes through the apical walland the upper end comprises an external hex, the external surface of theupper part of the body further comprising a drug delivery inlet on oneside below the external hex and a barrier ring below the drug deliveryinlet. a central lumen comprising parallel walls, defined by theinternal wall of the body of the device, wherein the central lumenextends from the upper part of the body to the lower part of the bodyand further communicates with the exterior through an inlet at the upperpart and through a plurality of holes that are sized to deliver drugs atthe required rate through the apical wall. threads on the externalsurface of the lower part of the device, wherein the threads are presentat the cervical third and the middle third of the part of the body belowthe level of the ring. an external hex at the top end of the deviceintended for holding and placement of the implant. a tubular inletcomprising external threads, located below the level of the external hexand at the side of the upper part of the device, wherein the inlet isintended for the attachment of a drug delivery tubing. a circular ringlocated below the level of the tubular inlet, comprising a convex andsmooth upper surface and a flat and smooth undersurface facing the bone,wherein the ring is intended to prevent the accidental inwarddisplacement of the implant into the maxillary sinus or the nasalcavity. a drug delivery tubing wherein the mesial end with internalthreads is intended for connection to the inlet on the implant and thedistal end with a nozzle is intended for connection to an external drugreservoir, wherein the drug reservoir is further connected to a druginfusion pump.
 3. The device of claim 2, wherein the device comprises abody in the form of a hollow, tapered tube with both the ends closed,wherein the apical end is rounded with a plurality of holes through theapical wall and the upper end comprises an external hex, the externalsurface of the upper part of the body further comprising a drug deliveryinlet on one side below the external hex and a barrier ring below thedrug delivery inlet. a central lumen comprising tapering walls, definedby the internal wall of the body of the device, wherein the centrallumen extends from the upper part of the body to the lower part of thebody and further communicates with the exterior through an inlet at theupper part and through a plurality of holes that are sized to deliverdrugs at the required rate through the apical wall. threads on theexternal surface of the lower part of the device, wherein the threadsare present at the cervical third of the part of the body below thelevel of the ring. an external hex at the top end of the device intendedfor holding and placement of the implant. a tubular inlet comprising asmooth external surface and internal threads, located below the level ofthe external hex and at the side of the upper part of the device,wherein the inlet may be angulated at varying degrees to the externalsurface of the upper part of the body of the device and is intended forthe attachment of a drug delivery tubing. a circular ring with flatsuperior and inferior surfaces comprising a plurality of holes throughthe ring near its peripheral margin, into which mini screws may bethreaded into for providing additional retention, wherein the ring islocated below the level of the tubular inlet and is intended forpreventing the accidental inward displacement of the implant into themaxillary sinus or the nasal cavity. a drug delivery tubing wherein thesmooth mesial end is intended for connection to the inlet on the implantand the distal end with a nozzle is intended for connection to anexternal drug reservoir, wherein the drug reservoir is further connectedto a drug infusion pump.
 4. The device of claim 2, wherein the drugdelivery inlet on the side of the implant comprises an opening withinternal threads.
 5. The drug delivery assembly in claim 1, wherein thedrug delivery assembly comprises an intra-implant part with a taperingbody comprising a central lumen with tapering walls defined by theinternal wall of the body, wherein the central lumen further opens tothe exterior through a the plurality of holes that are sized to deliverdrugs at the required rate through the apical wall, wherein theintra-implant part is intended for placement into the central lumen ofthe implant body. an outer tubular part extending from the side of theintra implant part, comprising a central lumen with parallel wallsdefined by the internal wall of the external tubing, the central lumenof the external tubing being further continuous with the central lumenof the intra implant part, wherein the mesial part of the externaltubing extending from the side of the intra implant part is intended forplacement into the vertical slot of the drug delivery inlet on theimplant. a nozzle at the distal, free end of the external tubing placedabove the level of the oral mucosa, intended for connection to anexternal drug reservoir and for ease of clinical access. a disposable,temporary cap for closing the nozzle when not in use.
 6. The device asclaimed in claim 1 wherein the device is in the form of a multiunitimplant comprising a body in the form of a hollow cylindrical tube withthe upper end open and the apical end closed, wherein the apical end isrounded with a plurality of holes through the apical wall and the upperend comprises a drug delivery inlet, the external surface of the upperpart of the body further comprising an external hex below the drugdelivery inlet and a barrier ring below the external hex. a centrallumen comprising tapering walls, defined by the internal wall of thebody of the device, wherein the central lumen communicates with theexterior through an inlet at the upper end and through a plurality ofholes that are sized to deliver drugs at the required rate through theapical wall. threads on the external surface of the lower part of thedevice, wherein the threads are present at the cervical third of thepart of the body below the level of the ring. an inlet located at theupper end of the device, comprising external threads at the cervicalthird and a vertical slot extending on one side of the body of the inletfrom the tip to the middle third, wherein the inlet is intended for theplacement of a drug delivery assembly into the central lumen of theimplant. an external hex located below the inlet at the upper part ofthe device, intended for holding and placement of the implant. acircular ring located below the level of the tubular inlet, comprising aconvex and smooth upper surface and a flat and smooth undersurfacefacing the bone, wherein the ring is intended to prevent the accidentalinward displacement of the implant into the maxillary sinus or the nasalcavity. a drug delivery assembly, wherein the mesial part of theexternal tubing extending from the side of the intra-implant part isslid into the vertical slot of the inlet on the implant, when thetapered intra-implant part is placed into the central lumen of theimplant body, further wherein the distal free end of the external tubingis intended for connection to an external drug reservoir attached to adrug infusion pump. a cap comprising an external hex at its upper partand internal threads at its lower part wherein the cap is intended forclosing the open inlet of the implant and to retain the drug deliveryassembly within the implant.
 7. The device as claimed in claim 1 whereinthe device is in the form of a multiunit implant comprising a body inthe form of a hollow cylindrical tube open at both the ends, wherein theopen apical end comprises beveled and outwardly flaring internal wallswith smooth and rounded margins and the open upper end comprises a drugdelivery inlet, the external surface of the upper part of the bodyfurther comprising an external hex below the drug delivery inlet and abarrier ring below the external hex. a central lumen comprising taperingwalls defined by the internal wall of the body of the device and limitedapically at the point where the internal wall flares outwards, whereinthe central lumen is located below the level of the apical margin of theimplant and communicates with the exterior through the open apex.threads on the external surface of the lower part of the device, whereinthe threads are present at the cervical third of the part of the bodybelow the level of the ring. an inlet located at the upper end of thedevice, comprising external threads at the cervical third and a verticalslot extending on one side of the body of the inlet from the tip to themiddle third, wherein the inlet is intended for the placement of a drugdelivery assembly into the central lumen of the implant. an external hexlocated below the inlet at the upper part of the device, intended forholding and placement of the implant. a circular ring located below thelevel of the tubular inlet, comprising a convex and smooth upper surfaceand a flat and smooth undersurface facing the bone, wherein the ring isintended to prevent the accidental inward displacement of the implantinto the maxillary sinus or the nasal cavity. a drug delivery assembly,wherein the mesial part of the external tubing extending from the sideof the intra-implant part is slid into the vertical slot of the inlet onthe implant, when the tapered intra-implant part is placed into thecentral lumen of the implant body, wherein the location of the tip ofthe intra-implant part is further defined by the apical limit of thecentral lumen and is therefore located below the apical margin of theimplant, further wherein the distal free end of the external tubing isintended for connection to an external drug reservoir attached to a druginfusion pump. a cap comprising an external hex at its upper part andinternal threads at its lower part wherein the cap is intended forclosing the open inlet of the implant and to retain the drug deliveryassembly within the implant.
 8. The device as claimed in claim 1 whereinthe device is in the form of a multiunit implant comprising a body inthe form of a hollow cylindrical tube with the upper end open and theapical end closed, wherein the apical end is rounded with a plurality ofholes through the apical wall and the upper end comprises a drugdelivery inlet with internal threads, the external surface of the upperpart of the body further comprising an external hex below the drugdelivery inlet and a barrier ring below the external hex. a centrallumen comprising tapering walls defined by the internal wall of the bodyof the device, wherein the central lumen communicates with the exteriorthrough an inlet at the upper end and through a plurality of holes thatare sized to deliver drugs at the required rate through the apical wall.threads on the external surface of the lower part of the device, whereinthe threads are present at the cervical third of the part of the bodybelow the level of the ring. an inlet located at the upper end of thedevice, comprising internal threads at the cervical third, wherein theinlet is intended for the placement of a drug delivery assembly into thecentral lumen of the implant. an external hex located below the inlet atthe upper part of the device, intended for holding and placement of theimplant. a circular ring located below the level of the tubular inlet,comprising a convex and smooth upper surface and a flat and smoothundersurface facing the bone, wherein the ring is intended to preventthe accidental inward displacement of the implant into the maxillarysinus or the nasal cavity. a drug delivery assembly comprising a taperedintra-implant part with a central lumen that opens to the exteriorthrough the plurality of holes that are sized to deliver drugs at therequired rate through the apical wall, the intra implant part furthercomprising an external drug delivery tubing attached to its upper endand external threads at its upper part, wherein the intra-implant partcomprising external threads is threaded into that part of the inlet ofthe implant that comprises internal threads, thereby adapting theexternal wall of the intra-implant part tightly to the internal walls ofthe implant except at the apical part, wherein a space exists at theapical part defined by outer wall of the apical part of theintra-implant part and the internal wall of the apical part of theimplant, into which the drug is initially delivered for further transferto the exterior through the plurality of holes through the apical wallof the implant, further wherein the distal end of the external tubing isintended for connection to an external drug reservoir attached to a druginfusion pump.
 9. The device as claimed in claim 1 wherein the device isin the form of a dental implant comprising a body in the form of ahollow cylindrical tube with an open upper end and a closed lower end,wherein the apical end is rounded with a plurality of holes through theapical wall and the upper end is open and comprises internal threads atthe cervical third, the body further comprising threads on the externalsurface of the body at the cervical third and middle third. a centrallumen within the body of the device defined by the surrounding internalwall which communicates to the exterior through a plurality of holesthat are sized to deliver drugs at the required rate through the apicalwall. an internal involute spline on the internal wall intended forassisting in holding and placement of the implant. an abutment with ahollow body comprising a smooth intra-oral part, an intra implant partwith an external involute spline and a barrier ring on the externalsurface of the body between the intra-oral part and the intra implant,the body further comprising a central lumen which extends from the intraoral part to the intra implant part of the body and is defined by theinternal wall of the body of the abutment, further wherein the centrallumen communicates to the exterior through the drug delivery tubing atthe coronal end and a plurality of holes that are sized to deliver drugsat the required rate through the apical wall. a cap comprising anexternal hex with a central hole at its upper part and external threadsat its lower part, intended for placement into the open end of theimplant comprising internal threads, wherein the cap retains theabutment within the implant.
 10. The device as claimed in claim 1wherein the device is in the form of a mini plate with a centralreservoir dial comprising, a hollow cylindrical reservoir dial with aclosed lower end comprising a plurality of holes that are sized todeliver drugs at the required rate through the apical wall, forming thebase and an open upper end comprising threads located internally at thecervical third, with limbs extending on the sides of the dial from themiddle part, further wherein the upper part of the body of the reservoirdial, above the level of the limbs is perpendicular to the base. a capmade of a resilient, biocompatible material that self-seals wheneverpenetrated by a needle, comprising a single row of a plurality of holesthat are spaced uniformly in a circular arrangement along the outermargin of the superior surface of the upper part and are intended forassisting in holding and placement, and a lower part with threadslocated externally intended for placement into the open part of thereservoir dial. limbs extending from the reservoir dial wherein thelimbs may be straight or L shaped comprising screw holes intended forplacement of screws for retention.
 11. The device as claimed in claim 10wherein the device is in the form of a mini plate with a centralreservoir dial comprising, a hollow cylindrical reservoir dial with aclosed lower end comprising a plurality of holes that are sized todeliver drugs at the required rate through the apical wall, forming thebase and an open upper end comprising threads located externally at thecervical third, with limbs extending on the sides of the dial from themiddle part, further wherein the upper part of the body of the reservoirdial, above the level of the limbs is angulated with respect to itsbase. a cap made of a resilient, biocompatible material that self-sealswhenever penetrated by a needle, comprising an upper part with a centralexternal hex intended for assisting in holding and placement, and alower part with threads located internally intended for placement ontothe open part of the reservoir dial. limbs extending from the reservoirdial wherein the limbs may be straight or L shaped comprising screwholes intended for placement of screws for retention.
 12. A method fordelivering drugs under the respiratory mucosa using the drug deliverysystem, for use in delivering a drug into the brain by bypassing theblood brain barrier, without causing any increase of the drug in theperipheral circulation, comprising the following steps elevating a fullthickness mucoperiosteal flap over the bone overlying the respiratorymucosa in the maxillary sinus or nasal cavity region, preferably fromthe buccal mucosal or the palatal mucosal region. using a bone trephinedrill of appropriate diameter and length to circumscribe a bone window.using the slowly rotating trephine drill to pry away the overlying bonewithout tearing the underlying respiratory mucosa or using apiezo-instrument to remove the circumscribed bone without tearing theunderlying respiratory mucosa. releasing and elevating the intactrespiratory mucosal lining from the bony margins and from thesurrounding walls using a soft tissue elevator of appropriate size andshape. placing the drug delivery device of required diameter and lengthinto the surgical site using the placement instruments, wherein theapical end of the implant comprising a plurality of holes is placedbeneath and in contact with connective tissue side of the respiratorymucosa. connecting the mesial end of the drug delivery tubing to theinlet on the implant and placing the distal free end of the tubing withthe nozzle at a level overlying the oral mucosa in the buccal sulcus, atthe buccal gingival sulcus or the palatal gingival sulcus. repositioningof the surgical flap and placement of sutures. allowing the surgicalsite to heal and the implanted device to osseointegrate adequately.after adequate healing, whenever drug delivery to the brain is required,the disposable cap of the nozzle at the free end of the tubing isremoved and the nozzle is connected to an external drug reservoirattached to an infusion pump. a drug that can be given in smallquantities without causing any systemic or local complications isdelivered in a continuous and controlled manner using the external druginfusion pump at a rate that does not cause backflow of the drug at theimplanted site or cause leakage and overflow across the overlyingmucosal lining.
 13. The method in claim 12, wherein drug is deliveredinto the brain by bypassing the blood brain barrier without causing anyincrease in the peripheral circulation through the following routeswherein the drug that is absorbed in the connective tissue of theoverlying respiratory mucosa, may be transferred through the neuralroute, vascular route, by the counter-current mechanism at the cavernoussinus or by the lymphatic route, into the brain by bypassing the bloodbrain barrier. the drug that is absorbed in the connective tissue of theoverlying respiratory mucosa, may also be engineered for uptake into thegoblet cell, for further secretion along with mucus by the goblet cellin the maxillary sinus lining epithelium if the clinical situationdemands more retention time on the respiratory mucosal epithelialsurface, wherein the drug may be further transported by mucociliaryaction over a larger area of respiratory mucosa for further absorptionin the maxillary sinus and nasal cavity.
 14. The method in claim 12,wherein the device is placed into the maxillary sinus with its apicaltip above the level of the respiratory lining mucosa for use indelivering a drug into the brain by bypassing the blood brain barrier,without causing any increase of the drug in the peripheral circulation,comprising the following steps elevating a full thickness mucoperiostealflap over the bone overlying the respiratory mucosa in the maxillarysinus or nasal cavity region, preferably from the buccal mucosal or thepalatal mucosal region. using a bone trephine drill of appropriatediameter and length to circumscribe a bone window. removing thecircumscribed bone with the trephine drill along with the underlyingrespiratory mucosa attached to the bone. placing the implant of requireddiameter and length into the surgical site using the placementinstruments, wherein the apical end of the implant comprising aplurality of holes is placed into the maxillary sinus and is locatedabove the level of the epithelial layer of the respiratory liningmucosa. connecting the mesial end of the drug delivery tubing to theimplant and placing the distal free of the tubing with the nozzle at alevel overlying the oral mucosa in the buccal sulcus, at the buccalgingival sulcus or the palatal gingival sulcus. repositioning of thesurgical flap and placement of sutures. allowing the surgical site toheal and the implanted device to osseointegrate adequately. afteradequate healing, whenever drug delivery to the brain is required, thedisposable cap of the nozzle at the free end of the tubing is removedand the nozzle is connected to an external drug reservoir attached to adrug infusion pump. a drug that is in the form of an inhalableformulation or that can be given in larger volumes without systemic orlocal complications is delivered in a continuous and controlled mannerusing the external drug infusion pump at a rate that does not causebackflow of the drug at the implanted site or cause leakage and overflowacross the overlying mucosal lining.
 15. The method in claim 14, whereindrug is delivered into the brain by bypassing the blood brain barrierwithout causing any increase in the peripheral circulation through thefollowing routes wherein as the normal maxillary sinus is emptied of airduring the inspiratory phase of the respiratory cycle, the drug which islocally delivered into the maxillary sinus is inhaled from the maxillarysinus during normal inspiration to reach the nasal respiratory mucosaand the olfactory mucosa, from where the drug is further absorbed intothe connective tissue for delivery into the brain through the neural,vascular or lymphatic route by bypassing the blood brain barrier. as thenormal maxillary sinus lining epithelial cells move the mucus throughthe ostium into the middle meatus and onto the nasal respiratory mucosa,the drug which is locally delivered into the maxillary sinus is movedacross the epithelial surface of the respiratory lining mucosa throughthe ostium into the middle meatus and onto the nasal respiratory mucosaresulting in increased retention time on the respiratory mucosal surfaceleading to absorption of increased quantity of the drug into theunderlying connective tissue and further delivery into the brain throughthe neural, vascular or lymphatic route by bypassing the blood brainbarrier.
 16. The drug infusion pump in claim 1, wherein the unitcomprises an external drug reservoir holding the therapeutic agentintended for delivery into the brain an electronically controlledexternal drug infusion pump capable of delivering drugs from thereservoir at a desired rate in a controlled and continuous manner,intended to deliver the therapeutic agent without causing eitherbackflow of drug at the surgical site wherein the device is implanted orleakage and overflow of the drug across the overlying mucosa.
 17. Thedrug infusion pump in claim 1, wherein an abutment intended forplacement into a drug delivery device in the form of a dental implant isused for providing controlled and continuous drug delivery atpredetermined rates and comprises of any one of the followingembodiments A hollow abutment comprising a drug reservoir located withinthe central lumen at the lower part of the body and an electronically orosmotically driven drug infusion pump located within the central lumenat the upper part of the body, intended for delivering the drug in acontinuous and controlled manner from the drug reservoir to theexterior, through a plurality of holes that are sized to deliver drugsat the required rate through the apical wall. A hollow abutment intendedfor use as a drug reservoir comprising a central lumen extending fromthe upper part of the body to its lower part defined by the internalwall of the body of the abutment, the lower part of the body furthercomprising a plurality of holes that are sized to deliver drugs in acontinuous manner at the required rate through the apical wall. A hollowabutment with a central lumen that opens to the exterior, at the upperend through an inlet comprising internal threads and at the apical endthrough a plurality of holes that are sized to deliver drugs at therequired rate through the apical wall, wherein the inlet at the upperend is intended for connecting a drug delivery tubing that is furtherconnected to an external reservoir attached to an external drug infusionpump, and the lower part is intended for placement into the hollow drugdelivery device in the form of a dental implant comprising a pluralityof holes that are sized to deliver drugs at the required rate throughthe apical wall and also correspond to the position of holes in theapical wall of the abutment.
 18. The therapeutic agent in claim 1,wherein the drug comprises drug molecules that may be sized to aid drugdelivery into the brain. have affinity to specific receptors in thebrain wherein the drug localizes at targeted sites.
 19. The instrumentkit in claim 1, wherein the kit comprises a hand held ratchet comprisinga head intended for adaption to the external hex on the implant and ahandle which may be either straight or angulated. a motor driven hexdriver comprising a head intended for adaption to the external hex onthe implant and a straight shank, wherein the free end of the shank isintended for placement into a rotary handpiece. a spanner comprising ahead intended for adaption to the external hex on the implant and ahandle which may be either straight or angulated. a driver comprising aplurality of projections at the free margins, wherein the projectionsare intended for placement into the holes of the retention cap. a capremover comprising a pair of claws with handles intended for holding themargins of the retention cap, a vertically moveable shank and a rotatingfinger rest on the top end of the shank.
 20. A method of drug delivery,wherein a natural tooth with its root tip in contact with therespiratory mucosa is used for delivering drugs into the brain bycomprising the following steps. Performing an access cavity at the crownpart of the tooth Extirpating the pulp and performing biomechanicalpreparation of the tooth and enlarging the pulp canals to appropriatesize till the apex. Preparing a vertical slot of the appropriatedimensions on the buccal or palatal wall of the crown of the tooth.Making an impression of the tooth. Designing a crown with an inlet onthe buccal or palatal wall, wherein the inlet comprises a cylindricaltube open at both the ends, the inlet comprising internal threads at theintraoral end and a smooth intra pulpal end which may be either straightor curved apically. Placing and positioning the crown on the tooth withthe cylindrical inlet placed into the vertical slot present on thetooth, wherein the lower margin of the inlet is located at the base ofthe vertical slot on the buccal or palatal wall so that the pulp cavitycan be accessed from the outside through the inlet. Closing the inletwith a disposable screw when not in use. Using a drug delivery tubing,to connect the inlet in the crown to an external drug reservoir attachedto a drug infusion pump, for controlled and continuous drug deliveryinto the pulp cavity of the tooth, whereby the drug is furthertransferred to the connective tissue side of the overlying respiratorymucosa through the apical foramina.